CORTICOSTEROIDS FOR COVID-19

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programmeEMERGENCIES

CASIRIVIMAB AND IMDEVIMAB FOR COVID-19

Clinical Management of COVID-19

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Learning objectives

At the end of this module, you will be able to:

• Describe what monoclonal antibodies are and how they work.

• Describe the role of casirivimab and imdevimab in the management of patients with COVID-19.

• Describe key casirivimab and imdevimab dosing and administration considerations for patients with COVID-19.

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Special note

Drugs and doses stated here are for illustrative purposes only.

Decisions regarding the use of any medication must be made by a licensed provider and take into account each patient's specific clinical history and other circumstances, and be in accordance with relevant local management and prescribing guidelines.

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casirivimab and imdevimab in COVID-19: summary of recommendations

In September 2021, the following WHO recommendations regarding casirivimab and imdevimab for patients with COVID-19 were released:

Conditional recommendation: We recommend treatment with casirivimab and imdevimab for patients with non-severe COVID-19 at highest risk for hospitalization and those with severe and critical COVID-19 who are seronegative for SARS-CoV-2.

Oxygen, corticosteroids and IL-6 receptor blockers have previously been recommended in patients with severe and critical COVID-19. We recommend severe and critical patients with seronegative status should now also receive casirivimab and imdevimab.

Therapeutics and COVID-19: living guideline (who.int)

Therapeutics and COVID-19: living guideline (magicapp.org)

https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2021.3

https://app.magicapp.org/#/guideline/nBkO1E

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casirivimab and imdevimab in COVID-19: recommendation

A living WHO guideline on drugs for covid-19. BMJ 2020;370:m3379. https://doi.org/10.1136/bmj.m3379

https://doi.org/10.1136/bmj.m3379

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Review of monoclonal antibodies and their function

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Monoclonal antibodies: overview

• Antibodies, or immunoglobulins, are protein molecules that serve as a core component of the immune system.

• Antibodies are produced by B cells, a type of white blood cell that originate from stem cells in the bone marrow.

• Antibodies bind to proteins on the surface of bacteria, viruses or other cells (antigens), to trigger immune an immune response that clears infections.

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Monoclonal Antibodies: overview (continued)

• Monoclonal antibodies (mAbs) have been developed for various pathogens, including RSV, MERS-CoV, Ebola and Zika virus.

• They are typically created by identifying pathogen specific B cells in patients recently recovered from an infection or by immunizing genetically modified mice and harvesting effective antibodies from them.

• Once B cells are identified the genes of immune globulin heavy and light chains are recovered and expressed to produce mAbswhich have activity against a predetermined target.

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Monoclonal Antibodies for COVID-19

• Most monoclonal antibody’s being developed for SARS-CoV-2 target the spike protein, which the virus utilizes to enter the host cells via the ACE-2 receptor.

• Casirivimab and imdevimab are two recombinant human monoclonal antibodies developed and studied for patients with COVID-19.

• Both antibodies targets a different part of the SARS-CoV-2 spike protein receptor binding domain.

• By binding to the SARS-CoV-2 spike protein, the virus is unable to attach to the human ACE-2 receptor and infection of the host cell is prevented.

• The half-life for both monoclonal antibodies ranges from 27 to 32 days.

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Reviewing process of developing recommendations for casirivimab and imdevimab

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casirivimab and imdevimab in COVID-19: guideline development process

• The WHO Therapeutics and COVID-19 Guideline Development Group (GDG), a group of international content experts, patients, clinicians, and methodologists with no conflicts of interest and balanced in terms of gender, geography, expertise, and patient representation met in July 2021.

• The GDG produced recommendations following standards for trustworthy guideline development using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation) in full compliance with the WHO Handbook for guideline development, 2nd edition.

• The GDG took an individual patient perspective to values and preferences.

A high value was placed on resource allocation, given the burden of pandemic for healthcare systems globally. Values considered include- Applicability- Balance of benefits and harms- Resource implications, feasibility, equity and human rights - Acceptability

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casirivimab and imdevimab in COVID-19: guideline development process

• Since 2020, WHO has worked with COVID- living network meta-analysis (COVID-LNMA), an international research initiative.

• The COVID-LNMA keeps a live mapping of registered trials and a living systematic review of trial results.

• Analysis of therapies such as casirivimab and imdevimab for COVID-19 were conducted and presented to the WHO guideline development group (GDG).

https://covid-nma.com/

https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=197242


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casirivimab and imdevimab for COVID-19:Conditional recommendation for use of monoclonal antibody

The GDG made a conditionalrecommendation for casirivimaband imdevimab in selected patients with COVID-19 based on moderate certainty of evidence in patients with non-severe disease and low certainty of evidence in patients with severe or critical disease.

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casirivimab and imdevimab for COVID-19:understanding the strength of recommendations

Conditional

• For patients: The majority of individuals would want the suggested course of action, but many would not.

• For clinicians: Different choices are likely to be appropriate for different patients and therapy should be tailored to the individual patient circumstances.

• For policymakers: Policy making will require substantial debates and involvement of many stakeholders. Policies are also likely to vary between regions.

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Evidence for Casirivimab and Imdevimab

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casirivimab and imdevimab for COVID-19:summary of evidence for non-severe disease

• Analysis of four trials that enrolled total of 4722 participants with non-severe COVID-19 revealed that casirivimab and imdevimab:

– probably reduces admission to hospital (moderate certainty evidence)

– probably reduce duration of hospitalization (best estimate of a reduction from 9.6 to 8.2 days; moderate certainty evidence)

– probably reduces time to symptom improvement (moderate certainty evidence)

– have trivial or no effect on mortality (moderate certainty evidence)

– have trivial or no effect on mechanical ventilation (moderate certainty evidence)


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casirivimab and imdevimab for COVID-19:Evidence in non-severe disease

The GDG made a conditionalrecommendation for casirivimaband imdevimab in patients with non-severe COVID-19 at highest risk for hospitalization.

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casirivimab and imdevimab for COVID-19:summary of evidence for severe and critical disease (seronegative)

• Analysis of evidence in patients with severe and critical COVID-19 from one trial of 9785 patients (RECOVERY) revealed that casirivimab and imdevimab:

– Reduces mortality risk in seronegative patients (moderate certainty of evidence, based on 3153 patients).

– Have very uncertain impact on mechanical ventilation and duration of hospitalization

• In patients who are seronegative, risk for mechanical ventilation reduces 13% (low certainty evidence).

Horby, Peter W., et al. "Casirivimab and imdevimab in patients admitted to hospital with COVID-

19 (RECOVERY): a randomised, controlled, open-label, platform trial." medRxiv (2021).

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casirivimab and imdevimab for COVID-19:evidence for severe and critical disease (seronegative)

The GDG made a conditionalrecommendation for casirivimab and imdevimab in patients with severe and critical COVID-19 who are seronegative for SARS-CoV-2.

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casirivimab and imdevimab for COVID-19:hypothesis and evidence about seronegative serostatus

• Casirivimab and imdevimab are antibodies that target SARS-CoV-2 spike protein.

• People who have been exposed to SARS-CoV-2 may produce their own anti-SARS-CoV-2 spike protein antibodies. If they have produced antibodies, the hypothesis is that they would be seropositive.

– It was postulated that administration might have differential effects in patients who have produced their own anti-SARS-CoV-2 spike protein antibodies (seropositive) compared with those who have not (seronegative).

• In the RECOVERY trial, analysis showed that administration of casirivimab and imdevimabhad more benefit in patients who were seronegative. This was a credible subgroup effect.

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Clinical considerations when administering casirivimab and imdevimab

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Who should get casirivimab and imdevimab: summary of recommendations

Patients with confirmed non-severe COVID-19 at

greater than 10% risk for progression of infection

and hospitalization*

Those at highest risk typically are:

1. Older

2. Have an immunodeficiency and/or chronic

disease

3. Unvaccinated

Patients with confirmed severe or critical COVID-

19 seronegative for SARS-CoV-2

*Serologic testing should be conducted with tests that

detect the presence of the SARS-CoV-2 spike protein

antibodies and have performance characteristics

similar to the reference standard test used to

characterize seronegative patients in the

RECOVERY trial

• Risk factors include: > 60 years old, hypertension, diabetes, cardiac disease, chronic lung disease,

cerebrovascular disease, dementia, mental disorders, chronic kidney disease, immunosuppression

(including HIV), obesity, cancer.

• In pregnancy risk factors include: advanced maternal age, high BMI, and chronic medical conditions.

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casirivimab and imdevimab for COVID-19:summary of recommendations (continued)

• At a time of drug shortage, it may be necessary to prioritize use of casirivimab and imdevimab.

• One possibility is to prioritize patients with the highest baseline risk for mortality (e.g. those with critical disease over those with severe disease).

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casirivimab and imdevimab for COVID-19:Why must patients with severe or critical disease be seronegative?

• Casirivimab and imdevimab are antibodies that target SARS-CoV-2 spike protein.

• People who have been exposed to SARS-CoV-2 may produce their own antibodies against the SARS-CoV-2 spike protein antibodies and may be seropositive.

• Casirivimab and imdevimab might have differential effects in patients who have produced their own anti-SARS-CoV-2 spike protein antibodies (seropositive) compared with those who have not (seronegative).

• It is hypothesized the effect of casirivimab and imdevimab might be greater, or restricted to, seronegative individuals who have not yet mounted an effective antibody response.

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casirivimab and imdevimab for COVID-19:serologic testing considerations

• Use a test with performance characteristics similar to the reference standard test used to characterize seronegative patients in the RECOVERY trial

• i.e. the Oxford fluorescent-based ELISA assay for serum IgG against the SARS-CoV- 2 spike protein, with an arbitrary cut-off determined by a panel of positive controls

• Some lateral flow assays may be suitable and can usually be performed in several minutes (36)(37)(38).

• Choose the most applicable test for your setting.

Add refence 36, 37, 38

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casirivimab and imdevimab in COVID-19: contraindications

• Allergy to casirivimab and imdevimab or components: L-Histidine, L-Histidine monohydrochloride monohydrate, polysorbate 80, sucrose

• Prior hypersensitivity to casirivimab or imdevimab

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casirivimab and imdevimab for COVID-19: dosing

• Casirivimab and Imdevimab can be administered as 1200– 8000 mg • (600 – 4000 mg of each antibody) demonstrating efficacy at all doses.

• Doses apply to individuals ≥ 12 years of age and weighing ≥ 40 kg.

Drug Dose

(Non-Severe COVID-19)

Dose

(Severe and Critical COVID-19)

Casirivimab 600 mg IV infusion or subcutaneous

OR

1200 mg IV infusion

1200 mg or 4000 mg IV infusion

Imdevimab 600 mg IV infusion or subcutaneous

OR

1200 mg IV infusion


Total 1200-2400 mg IV infusion

OR

1200 mg subcutaneous

* If administered subcutaneously, the maximum

dose is 1200 mg (600 mg each drug)


The drugs and doses stated here are for illustrative purposes only. Decisions regarding the use of any medication must be made by a licensed provider and take into account each patient's specific clinical history and other circumstances, and be in accordance with relevant local management and prescribing guidelines.

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casirivimab and imdevimab for COVID-19:choosing a dose and administration route (1/2)

• Four clinical trials that were used to make the WHO recommendation used IV administration route.

– Subcutaneous dose has been studied in prophylactic studies.

• Total doses ranged between 1200 mg to 8000 mg among the trials.

• Efficacy found at all tested doses.

• If priority is to ensure maximum effectiveness in every individual who receives treatment, one might choose the higher total dose and IV administrations.

• If priority is to ensure giving as many people as possible the opportunity to benefit from treatment (in the face of difficulties in widespread IV administration in the community for example), one might choose the lower total dose and ensure the availability of SQ administration as an alternative.

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casirivimab and imdevimab for COVID-19:choosing a dose and administration route (2/2)

• One trial (RECOVERY) used to make the WHO recommendation used IV administration at total dose 8000mg.

– This trial was in patients with severe or critical COVID-19.

• Pharmacokinetic data from patients with non-severe COVID-19 demonstrate therapeutics thresholds can be reached at total dose of 1200 mg and above.

• If priority is to ensure maximum effectiveness in every individual who receives treatment, and minimize risk of emergence of resistance, one might choose the higher IV total dose (8000 mg).

• If one’s priority is to ensure giving as many people as possible the opportunity to benefit from treatment (in the face of difficulties in widespread IV administration in the community for example), one might choose the lower IV total dose (2400 mg).

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casirivimab and imdevimab in COVID-19: route of delivery

The drugs and doses stated here are for illustrative purposes only. Decisions regarding the use of any medication must be made by a licensed provider and take into account each patient's specific clinical history and other circumstances, and be in accordance with relevant local management and prescribing guidelines.

• For COVID-19, casirivimab and imdevimab should be given together.

• The medication can be given intravenously (IV) or subcutaneously (SC).

Preferred: Casirivimab and imdevimab intravenous single infusion should be administered

using a dedicated IV line with a sterile low protein binding in-line or add-on 0.2 micron filter

via pump (preferred) or gravity.

Alternative: Casirivimab and imdevimab may be administered by subcutaneous injection via

syringes when it is unable to be given by intravenous infusion and would lead to a delay in

treatment.

https://www.regeneron.com/downloads/treatment-covid19-eua-fact-sheet-for-hcp.pdf

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casirivimab and imdevimab for COVID-19:Preparation (Intravenous)

1. Remove casirivimab and imdevimab vials from refrigerator and allow to equilibrate to room temperature for 20 minutes prior to

preparation.

- Ensure there is no discoloration or particulate matter of the product prior to administration. If observed then discard.

2. Obtain a prefilled intravenous infusion bag of sodium chloride or dextrose solution. *

3. To allow for space in the infusion bag for the addition of the casirivimab and imdevimab, use a syringe and aseptic non-touch technique

to withdraw the total volume dose equivalent from the infusion bag and discard.

- For example, if preparing a total dose of casirivimab and imdevimab of 1200 mg infusion, remove 10 mL of fluid from the infusion bag prior

to injecting the monoclonal antibody

4. Using a separate syringe for each vial of casirivimab and imdevimab, withdraw the appropriate amount of each product from the

respective vial and inject into the prefilled infusion bag.

5. Gently invert infusion bag by hand ten times to mix and then immediately administer.

- If unable to immediately administer infusion solution, then store in refrigerator at 2-8° C for up to 36 hours**

- May also store at room temperature (25° C) for no more than 4 hours

* Infusion bag may be 50mL, 100 mL, 150 mL, or 200 mL of 0.9% sodium chloride or 5% dextrose injection

** If refrigerated, remove 30 minutes prior to patient infusion to allow for equilibration to room temperature

The drugs and doses stated here are for illustrative purposes only. Decisions regarding the use of any medication must be made by a licensed provider and take into account each patient's specific clinical history and other circumstances, and be in accordance with relevant local management and prescribing guidelines.https://www.regeneron.com/downloads/treatment-covid19-eua-fact-sheet-for-hcp.pdf

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casirivimab and imdevimab for COVID-19:preparation (intravenous – dilution instructions)

Size of prefilled infusion bag Preparing casirivimab and imdevimab using individual vials

50 mL Into a prefilled 0.9% sodium chloride or 5% dextrose infusion bag inject

• 5 mL of casirivimab

(Use two 6-mL single use vials OR one 20-mL multidose vial)

PLUS

• 5 mL of imdevimab

(Use two 6-mL single use vials OR one 20-mL multidose vial)

100 mL

150 mL

200 mL



• 10 mL of casirivimab

(Use four 6-mL single use vials OR one 20-mL multidose vial)

PLUS

• 10 mL of imdevimab

(Use four 6-mL single use vials OR one 20-mL multidose vial)

100 mL

150 mL

200 mL



• 33.3 mL of casirivimab

(Use three 20-mL multidose vial)

PLUS

• 33.3 mL of imdevimab

(Use three 20-mL multidose vial)

250 mL

500 mL

Table 1: Dilution instructions for casirivimab 600 mg + imdevimab 600 mg for intravenous infusion (Total Dose 1200 mg)




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casirivimab and imdevimab for COVID-19:preparation (subcutaneous)

1. Remove casirivimab and imdevimab vials from the refrigerator and allow to

equilibrate to room temperature for 20 minutes prior to preparation.

- Ensure there is no discoloration or particulate matter of the product prior to

administration. If observed then discard.

2. Subcutaneous injection of casirivimab and imdevimab should be administered

consecutively using the appropriate number of syringes.*

3. Withdraw the appropriate amount of casirivimab and imdevimab into each syringe

and then replace the transfer needle with a 25- guage to 27-guage needle for

subcutaneous injection.

4. Immediately administer the product

- If unable to immediately administer, the prepared syringes can be stored at room

temperature for up to 4 hours.

* Use 3-mL or 5-mL polyprophylene luer lock syringes with a luer connection and a 21

guage 1 ½ inch transfer needle

* A maximum dose of casirivimab 600 mg + imdevimab 600 mg (Total dose 1200 mg

subcutaneous)


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casirivimab and imdevimab for COVID-19:administration (intravenous)

Casirivimab and imdevimab should be administered

by a qualified healthcare professional in a monitored

setting using septic non touch technique.

Materials needed

- Polyvinyl chloride or polyurethane infusion set

- In-line or add-on low protein binding 0.2 micron

polyethersulfone (PES) filter

1. Attach the infusion set to the infusion bag

2. Prime the infusion set

3. Administer the entire infusion solution in the

infusion bag via pump or gravity through an

intravenous line containing a sterile in-line or add-on

0.2 micron filter

4. Do NOT administer the infusion solution with

another medication

5. Once the infusion is complete, flush the line with

0.9% sodium chloride or 5% dextrose injection

6. Clinically monitor patient during and for one hour

post infusion

- BP, HR, RR, Temp, Oxygen Saturation

- 15 min, 30 min, and one hour after injection

The information stated here are for illustrative purposes only. Decisions regarding the use of any medication must be made by a licensed provider and take into account each patient's specific clinical history and other circumstances, and be in accordance with relevant local management and prescribing guidelines. https://www.regeneron.com/downloads/treatment-covid19-eua-fact-sheet-for-hcp.pdf

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casirivimab and imdevimab for COVID-19: administration (intravenous)

Size of Prefilled Infusion Bag Maximum Infusion Rate Minimum Infusion Time

50 mL 150 mL/hour 20 minutes


150 mL450 mL/hour 20 minutes


Table 1: Administration rate for casirivimab 600 mg + Imdevimab 600 mg for intravenous infusion (total dose 1200 mg)






Table 2: Administration rate for casirivimab 1200 mg + imdevimab 1200 mg for intravenous infusion (total dose 2400 mg)

Table 3: Administration rate for casirivimab 4000 mg + imdevimab 4000 mg for intravenous infusion (total dose 8000 mg)





The information stated here are for illustrative purposes only. Decisions regarding the use of any medication must be made by a licensed provider and take into account each patient's specific clinical history and other circumstances, and be in accordance with relevant local management and prescribing guidelines. https://www.regeneron.com/downloads/treatment-covid19-eua-fact-sheet-for-hcp.pdf

Infusion should NOT

be administered > 4 hours

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casirivimab and imdevimab for COVID-19:administration (subcutaneous)

1. Administer subcutaneous injection of casirivimab and imdevimab consecutively

and at a different injection site in the

- Thigh

- Abdomen

- Upper Arm

Maximum total dose is 1200 mg

2. Areas to avoid include

- Waistline

- Two inches around the navel

- Skin that is tender, tender, damaged, bruised, or scarred

3. Monitor patient for 1 hour after injection

- Blood pressure, heart rate, respiratory rate, temperature, oxygen saturation

- 15 min, 30 min, and one hour after injection

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casirivimab and imdevimab for COVID-19:patient monitoring

Hypersensitivity - Serious hypersensitivity reactions, including anaphylaxis has been reported with casirivimab and imdevimab

- Hypersensitivity reactions occurring > 24 hours after administration of casirivimab and imdevimab have been reported

- If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occurs, immediately discontinue the infusion and initiate appropriate medications,

supportive therapy, and airway management

Management of anaphylaxis- Severe allergic reactions can cause swelling of the airway and lead to obstruction.

- Give intramuscular adrenaline for airway obstruction, severe wheezing, or shock (Since adrenaline can wear off in minutes be prepared to administer additional doses).

- Make sure the patient as a IV and administer intravenous fluids while continuing to reassess the airway and administering oxygen as needed

- If patient has severe anaphylaxis or is not improving, consider transferring to a higher level of care for further management.

- Further details on basic emergency care can be accessed at https://www.who.int/publications/i/item/basic-emergency-care-approach-to-the-acutely-ill-and-injured

Infusion related reactions- Infusion related reactions occurring during infusion and up to 24 hours post infusion have been observed.

- They may be severe or life-threatening and you should consider slowing or stopping the infusion and providing appropriate medications and/or supportive care.

- These reactions may include

- Fever - Reduced Oxygenation - Difficulty Breathing - Headache - Nausea

- Angioedema - Chills - Throat Irritation - Fatigue - Bronchospasm

- Dizziness - Diaphoresis - Irregular Heart Beat - Hypertension - Pre-Syncope and Syncope

- Chest Pain or Discomfort - Hypotension - Weakness - Rash/Pruritis - Muscle Aches

Monitor patients during infusion and for one hour once completed.

They should have blood pressure, heart rate, respiratory rate, temperature and oxygen saturation checked at 15 minutes, 30 minutes, and

one hour post –infusion.

https://www.who.int/publications/i/item/basic-emergency-care-approach-to-the-acutely-ill-and-injured

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casirivimab and imdevimab for COVID-19:post-marketing surveillance and other considerations

Reporting of adverse events- Report all adverse events to WHO via medsafe application

- Report all adverse events to the manufacturer: www.roche.com/products/local_safety_reporting/htm

COVID-19 vaccine administration- As a precautionary measure, vaccination for SARS-CoV-2 should be deferred for ≥ 90 days in people who have received casirivimab and imdevimab. The

antibody treatment may interfere with vaccine-induced immune responses.

Special populations to monitor- Limited data regarding the use of casirivimab and imdevimab in pregnant women with COVID-19.

- The use of casirivimab and imdevimab should be used in pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

- There is no available data on the presence of casirivimab and imdevimab in human or animal milk, the effects on the breastfed infant, or the effect of the

drug on milk production.

http://www.roche.com/products/local_safety_reporting/htm

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Summary

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casirivimab and imdevimab for COVID-19:Summary

• Give casirivimab and imdevimab to patients with confirmed non-severe COVID-19 at risk for progression of infection and hospitalization

• Give casirivimab and imdevimab along with oxygen, systemic corticosteroids and IL-6RB for patients who are seronegative and have severe and critical COVID-19.

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References

1. World Health Organization. WHO handbook for guideline development. World Health Organization, 2014. https://apps.who.int/iris/handle/10665/145714

2. WHO Guideline Development Group Living Guidelines for COVID-19: Expert biographieshttps://www.who.int/publications/m/item/who-guideline-development-group-living-guidelines-for-covid-19-biographies

3. WHO: Therapeutics and COVID-19: Living guideline. Published 6 July 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2021.2

4. MAGICapp, ‘WHO Living Guidelines: Therapeutics and COVID-19, v3.1. Published 7 July 2021. https://app.magicapp.org/#/guideline/5486

5. A living WHO guideline on drugs for covid-19. BMJ 2020;370:m3379. Published 7 July 2021. https://www.bmj.com/content/370/bmj.m3379

https://apps.who.int/iris/handle/10665/145714

https://www.who.int/publications/m/item/who-guideline-development-group-living-guidelines-for-covid-19-biographies

https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2021.2

https://app.magicapp.org/

https://www.bmj.com/content/370/bmj.m3379

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Acknowledgements

ContributorsDr Janet Diaz, WHO, Geneva, Switzerland Dr Pryanka Relan, WHO, Geneva, SwitzerlandDr Krutika Kuppalli, WHO, Geneva, SwitzerlandMs Vanessa Cramond, WHO, Geneva, Switzerland

Documents

CORTICOSTEROIDS FOR COVID-19